Macrophages are bone marrow-derived cells that form an important part of the host defense system. They play a role in physiological as well as pathological processes, such as inflammation, fibrosis atherogenesis, and tumor invasion.
Macrophages are relatively large (10-20 .mu.m), long-lived, amoeboid, phagocytic and pinocytotic cells present in blood, lymph and other tissues. They are derived from monocytes which form a pool of precursors migrating from blood into peripheral tissues such as liver, spleen, lung, lymph nodes, peritoneum, skin, brain and bone, where they differentiate into macrophages with organ specific features. Macrophages play important roles in host resistance to a variety of pathogenic microorganisms, having important functions in, for example, phagocytosis, inflammation, antibody formation, cell-mediated cytotoxicity and delayed hypersensitivity.
In this regard, the major characteristic of macrophages is their ability to recognize, internalize and destroy a variety of foreign and endogenous substances and, thus, to function as scavengers that engulf pathogenic organisms, such as bacteria, parasites and viruses. Macrophages also remove extravasated blood cells or dead cells in tissues and, thereby, participate in the maintenance of tissues. Furthermore, macrophages are thought to play a role in immune response by presenting foreign antigens (i.e., are antigen-presenting cells) to lymphocytes. The macrophages have been shown to be able to bind "nonself" pathogens directly, or they recognize pathogens as foreign because they have been coated by antibodies or complement. The exact recognition mechanism is unknown, but it has been proposed that receptors with broad binding specificity are used to discriminate between self and nonself.
Scavenger receptors are macrophage cell membrane proteins that can bind a variety of substances and facilitate their uptake and removal from blood or connective tissue (see Krieger and Hertz, Ann. Rev. Biochem. 63, 601-637, 1994). The macrophage scavenger receptors have been suggested to play a role in the binding of foreign antigens, in addition to their apparently important role in atherogenesis. These receptors have unusually broad ligand binding specificity and, thus, differ from many other cell surface receptors.
Scavenger receptors of types I and II are trimeric membrane proteins with a small N-terminal intracellular domain, a transmembrane domain, and an extracellular portion containing a short spacer domain, an .alpha.-helical coiled coil domain, and a short triple-helical collagenous domain (Krieger and Hertz, Ann. Rev. Biochem., 63,601-637, 1994).
The type I scavenger receptor differs from the type II scavenger receptor in that it contains an additional C-terminal cysteine-rich domain. These receptors, which are present in macrophages in diverse tissues, such as liver and lung, have been shown to bind a variety of ligands such as chemically modified lipoproteins and albumin, polyribonucleotides, polysaccharides, phospholipids, asbestos etc. It has been proposed that the scavenger receptors play a key role in the development of atherosclerosis where they mediate macrophage uptake of modified low density lipoproteins (LDL) in arterial walls. Furthermore, the scavenger receptors are likely to function in host defense as some forms of gram-negative bacterial endotoxin and gram-positive bacteria can serve as their ligands. The collagenous domain of the scavenger receptor has been shown to mediate the binding activities assigned to these receptors.
The collagenous domain of the scavenger receptor is a triple helix formed by three chains which contain 24 consecutive Gly-Xaa-Yaa-triplets. Such Gly-Xaa-Yaa-triplets are the hallmark of the .alpha. chains of collagens, which are a family of extracellular proteins constituting the major structural proteins of the extracellular matrix. There are several proteins without structural functions that contain collagenous domains. As the scavenger receptors, most of those belong to the host defense mechanisms, such as complement factor C1q, conglutinin, mannose binding proteins, and pulmonary surfactant associated proteins. All these proteins are thought to participate in the removal of extracellular debris such as pathogenic material. Furthermore, enzymes such as acetyl cholinesterase and bacterial pullulanase contain collagenous domains.
Along these lines, applicants have identified and characterized a novel and unique macrophage receptor with collagenous structure. This protein, which shows structural homology with scavenger receptor type I, was expressed strongly after birth in a subset of macrophages in mouse spleen and lymph nodes. Furthermore, it is expressed in peritoneal macrophages, but not by macrophages of the liver or lung. The receptor was shown to bind bacteria and acetylated LDL, but not yeast. Based on its binding activity and distribution, the biological role of this receptor is believed to be related with immune defense and/or phagocytosis. The results suggest that the novel protein discovered by applicants is a macrophage-specific membrane receptor which has a role in host defense as it is expressed after birth in subpopulation of macrophages that are considered responsible for the binding of bacterial antigens and phagocytosis.